title: Long-term efficacy of ciliary muscle gene transfer of three sFlt-1 variants in a rat model of laser-induced choroidal neovascularization.
abstract: Inhibition of vascular endothelial growth factor (VEGF) has become the standard of care for patients presenting with wet age-related macular degeneration. However, monthly intravitreal injections are required for optimal efficacy. We have previously shown that electroporation enabled ciliary muscle gene transfer results in sustained protein secretion into the vitreous for up to 9 months. Here, we evaluated the long-term efficacy of ciliary muscle gene transfer of three soluble VEGF receptor-1 (sFlt-1) variants in a rat model of laser-induced choroidal neovascularization (CNV). All three sFlt-1 variants significantly diminished vascular leakage and neovascularization as measured by fluorescein angiography (FA) and flatmount choroid at 3 weeks. FA and infracyanine angiography demonstrated that inhibition of CNV was maintained for up to 6 months after gene transfer of the two shortest sFlt-1 variants. Throughout, clinical efficacy was correlated with sustained VEGF neutralization in the ocular media. Interestingly, treatment with sFlt-1 induced a 50% downregulation of VEGF messenger RNA levels in the retinal pigment epithelium and the choroid. We demonstrate for the first time that non-viral gene transfer can achieve a long-term reduction of VEGF levels and efficacy in the treatment of CNV.
authors.affiliation: 1] INSERM, UMRS 872 Physiopathology of Ocular Diseases: Therapeutic Innovations, Paris, France [2] Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMRS 872, Paris, France [3] Université Paris Descartes, UMRS 872, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: El Sanharawi
authors.forename: E
authors.initials: E
authors.lastname: Touchard
authors.forename: R
authors.initials: R
authors.lastname: Benard
authors.forename: P
authors.initials: P
authors.lastname: Bigey
authors.forename: V
authors.initials: V
authors.lastname: Escriou
authors.forename: C
authors.initials: C
authors.lastname: Mehanna
authors.forename: M-C
authors.initials: MC
authors.lastname: Naud
authors.forename: M
authors.initials: M
authors.lastname: Berdugo
authors.forename: J-C
authors.initials: JC
authors.lastname: Jeanny
authors.forename: F
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000818:Animals; D002460:Cell Line; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D002924:Ciliary Body / Q000378:metabolism*; D004195:Disease Models, Animal; D018274:Electroporation; D005260:Female; D005451:Fluorescein Angiography; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000628:therapy; D010957:Plasmids; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D014162:Transfection / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1